tbuckley/cabot-search huggingface dataset:
High-dimensional analysis of 16 SARS-CoV-2 vaccine combinations reveals lymphocyte signatures correlating with immunogenicity
Authors: Nicolás Gonzalo Nuñez, Jonas Schmid, Laura Power, Chiara Alberti, Sinduya Krishnarajah, Stefanie Kreutmair, Susanne Unger, Sebastián Blanco, Brenda Konigheim, Constanza Marín, Luisina Onofrio, Jenny Christine Kienzler, Sara Costa-Pereira, Florian Ingelfinger, Fabio Cerbán, Laura Chiapello, Carolina Montes, Cristina Motrán, Jeremías Dutto, Laura Almada, Lucía Boffelli, Lorena Spinsanti, Adrián Díaz, María Elisa Rivarola, Javier Aguilar Bioq, Mauricio Beranek, Marina E. Pasinovich, Juan M. Castelli, Carla Vizzotti, Maximilian Schaefer, Juan Villar-Vesga, Sarah Mundt, Carla Helena Merten, Aakriti Sethi, Tobias Wertheimer, Mirjam Lutz, Danusia Vanoaica, Claudia Sotomayor, Adriana Gruppi, Christian Münz, Diego Cardozo, Gabriela Barbás, Laura Lopez, Paula Carreño, Gonzalo Castro, Elias Raboy, Sandra Gallego, Gabriel Morón, Laura Cervi, Eva V. Acosta Rodriguez, Belkys A. Maletto, Mariana Maccioni, Burkhard Becher
Journal: Nature Immunology (2023)

Abstract The range of vaccines developed against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) provides a unique opportunity to study immunization across different platforms. In a single-center cohort, we analyzed the humoral and cellular immune compartments following five coronavirus disease 2019 (COVID-19) vaccines spanning three technologies (adenoviral, mRNA and inactivated virus) administered in 16 combinations. For adenoviral and inactivated-virus vaccines, heterologous combinations were generally more immunogenic compared to homologous regimens. The mRNA vaccine as the second dose resulted in the strongest antibody response and induced the highest frequency of spike-binding memory B cells irrespective of the priming vaccine. Priming with the inactivated-virus vaccine increased the SARS-CoV-2-specific T cell response, whereas boosting did not. Distinct immune signatures were elicited by the different vaccine combinations, demonstrating that the immune response is shaped by the type of vaccines applied and the order in which they are delivered. These data provide a framework for improving future vaccine strategies against pathogens and cancer.
Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis
Authors: Andrew J. Kwok, Alice Allcock, Ricardo C. Ferreira, Eddie Cano-Gamez, Madeleine Smee, Katie L. Burnham, Yasemin-Xiomara Zurke, Alex Novak, Melanie Darwent, Tanya Baron, Charlotte Brown, Sally Beer, Alexis Espinosa, Tine Panduro, Dominique Georgiou, Jose Martinez, Hannah Thraves, Elena Perez, Rocio Fernandez, Alberto Sobrino, Veronica Sanchez, Rufino Magallano, Karen Dineen, Jean Wilson, Stuart McKechnie, Alexander J. Mentzer, Claudia Monaco, Irina A. Udalova, Charles J. Hinds, John A. Todd, Emma E. Davenport, Julian C. Knight
Journal: Nature Immunology (2023)

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.
Annals of the Rheumatic Diseases collection on lupus nephritis (2019–2022): novel insights and advances in therapy
Authors: Myrto Kostopoulou, Antonis Fanouriakis, George Bertsias, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2023)

No single organ has received as much attention in systemic lupus erythematosus (SLE) as the kidneys. During the period 2019–2022, the Annals of the Rheumatic Diseases published several original papers, brief reports and letters that further elucidate the pathogenesis and advance the management of LN. A selection of representative original papers is highlighted in this review.
Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis
Authors: Yavuz F. Yazicioglu, Eros Marin, Ciaran Sandhu, Silvia Galiani, Iwan G. A. Raza, Mohammad Ali, Barbara Kronsteiner, Ewoud B. Compeer, Moustafa Attar, Susanna J. Dunachie, Michael L. Dustin, Alexander J. Clarke
Journal: Nature Immunology (2023)

Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
Targeting DNA polymerase β elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia
Authors: Ji-Yuan Teng, Ding-Peng Yang, Chao Tang, Hou-Shun Fang, Hui-Ying Sun, Yue-Ning Xiang, Xiao-Meng Li, Fan Yang, Rui-Xue Xia, Fu Fan, Jingjing Liu, Jiyang Yu, Jin-Chuan Hu, Ben-Shang Li, Hui Li, Fei-Long Meng, Cai-Wen Duan, Bin-Bing S. Zhou
Journal: Leukemia (2023)
Functional brain networks reflect spatial and temporal autocorrelation
Authors: Maxwell Shinn, Amber Hu, Laurel Turner, Stephanie Noble, Katrin H. Preller, Jie Lisa Ji, Flora Moujaes, Sophie Achard, Dustin Scheinost, R. Todd Constable, John H. Krystal, Franz X. Vollenweider, Daeyeol Lee, Alan Anticevic, Edward T. Bullmore, John D. Murray
Journal: Nature Neuroscience (2023)
Computational complexity drives sustained deliberation
Authors: Tao Hong, William R. Stauffer
Journal: Nature Neuroscience (2023)

Abstract Economic deliberations are slow, effortful and intentional searches for solutions to difficult economic problems. Although such deliberations are critical for making sound decisions, the underlying reasoning strategies and neurobiological substrates remain poorly understood. Here two nonhuman primates performed a combinatorial optimization task to identify valuable subsets and satisfy predefined constraints. Their behavior revealed evidence of combinatorial reasoning—when low-complexity algorithms that consider items one at a time provided optimal solutions, the animals adopted low-complexity reasoning strategies. When greater computational resources were required, the animals approximated high-complexity algorithms that search for optimal combinations. The deliberation times reflected the demands created by computational complexity—high-complexity algorithms require more operations and, concomitantly, the animals deliberated for longer durations. Recurrent neural networks that mimicked low- and high-complexity algorithms also reflected the behavioral deliberation times and were used to reveal algorithm-specific computations that support economic deliberation. These findings reveal evidence for algorithm-based reasoning and establish a paradigm for studying the neurophysiological basis for sustained deliberation.
Risk of severe outcomes among SARS-CoV-2 Omicron BA.4 and BA.5 cases compared to BA.2 cases in England
Authors: Nurin Abdul Aziz, Sophie Grace Nash, Asad Zaidi, Tommy Nyberg, Natalie Groves, Russell Hope, Jamie Lopez Bernal, Gavin Dabrera, Simon Thelwall
Journal: Journal of Infection (2023)
Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience
Authors: Joe C. Udeochu, Sadaf Amin, Yige Huang, Li Fan, Eileen Ruth S. Torres, Gillian K. Carling, Bangyan Liu, Hugo McGurran, Guillermo Coronas-Samano, Grant Kauwe, Gergey Alzaem Mousa, Man Ying Wong, Pearly Ye, Ravi Kumar Nagiri, Iris Lo, Julia Holtzman, Carlo Corona, Allan Yarahmady, Michael T. Gill, Ravikiran M. Raju, Sue-Ann Mok, Shiaoching Gong, Wenjie Luo, Mingrui Zhao, Tara E. Tracy, Rajiv R. Ratan, Li-Huei Tsai, Subhash C. Sinha, Li Gan
Journal: Nature Neuroscience (2023)

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.
Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin
Authors: Xiaofei Li, Zaneta Andrusivova, Paulo Czarnewski, Christoffer Mattsson Langseth, Alma Andersson, Yang Liu, Daniel Gyllborg, Emelie Braun, Ludvig Larsson, Lijuan Hu, Zhanna Alekseenko, Hower Lee, Christophe Avenel, Helena Kopp Kallner, Elisabet Åkesson, Igor Adameyko, Mats Nilsson, Sten Linnarsson, Joakim Lundeberg, Erik Sundström
Journal: Nature Neuroscience (2023)

Abstract The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5–12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.
Single cell landscape of parietal epithelial cells in healthy and diseased states
Authors: Wen-bin Liu, Guang-rui Huang, Bao-li Liu, Hai-kun Hu, Jie Geng, Hong-liang Rui, Chang Gao, Yu-jiao Huang, Gui-yang Huo, Jia-rong Mao, Chuan-jian Lu, An-long Xu
Journal: Kidney International (2023)

The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis.
Durability of neutralizing RSV antibodies following nirsevimab administration and elicitation of the natural immune response to RSV infection in infants
Authors: Deidre Wilkins, Yuan Yuan, Yue Chang, Anastasia A. Aksyuk, Beatriz Seoane Núñez, Ulrika Wählby-Hamrén, Tianhui Zhang, Michael E. Abram, Amanda Leach, Tonya Villafana, Mark T. Esser
Journal: Nature Medicine (2023)

Abstract Nirsevimab is an extended half-life monoclonal antibody specific for the prefusion conformation of the respiratory syncytial virus (RSV) F protein, which has been studied in preterm and full-term infants in the phase 2b and phase 3 MELODY trials. We analyzed serum samples collected from 2,143 infants during these studies to characterize baseline levels of RSV-specific immunoglobulin G antibodies and neutralizing antibodies (NAbs), duration of RSV NAb levels following nirsevimab administration, the risk of RSV exposure during the first year of life and the infant’s adaptive immune response to RSV following nirsevimab administration. Baseline RSV antibody levels varied widely; consistent with reports that maternal antibodies are transferred late in the third trimester, preterm infants had lower baseline RSV antibody levels than full-term infants. Nirsevimab recipients had RSV NAb levels &gt;140-fold higher than baseline at day 31 and remained &gt;50-fold higher at day 151 and &gt;7-fold higher at day 361. Similar seroresponse rates to the postfusion form of RSV F protein in nirsevimab recipients (68–69%) compared with placebo recipients (63–70%; not statistically significant) suggest that while nirsevimab protects from RSV disease, it still allows an active immune response. In summary, nirsevimab provided sustained, high levels of NAb throughout an infant’s first RSV season and prevented RSV disease while allowing the development of an immune response to RSV.
Siglec-9 is an inhibitory receptor on human mast cells in vitro
Authors: Irina Miralda, Nyssa B. Samanas, Albert J. Seo, Jake S. Foronda, Josie Sachen, Yvonne Hui, Shane D. Morrison, Carole A. Oskeritzian, Adrian M. Piliponsky
Journal: Journal of Allergy and Clinical Immunology (2023)
Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis
Authors: Andrew C. Brown, Carla J. Cohen, Olga Mielczarek, Gabriele Migliorini, Félicie Costantino, Alice Allcock, Connor Davidson, Katherine S. Elliott, Hai Fang, Alicia Lledó Lara, Alice C. Martin, Julie A. Osgood, Anna Sanniti, Giuseppe Scozzafava, Matteo Vecellio, Ping Zhang, Mary Helen Black, Shuwei Li, Dongnhu Truong, Julio Molineros, Trevor Howe, B. Paul Wordsworth, Paul Bowness, Julian C. Knight
Journal: Cell Genomics (2023)

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14
Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections
Authors: Peter T. Buckley, Rita Chan, Jeffrey Fernandez, Jinquan Luo, Keenan A. Lacey, Ashley L. DuMont, Aidan O’Malley, Randall J. Brezski, Songmao Zheng, Thomas Malia, Brian Whitaker, Adam Zwolak, Angela Payne, Desmond Clark, Martin Sigg, Eilyn R. Lacy, Anna Kornilova, Debra Kwok, Steve McCarthy, Bingyuan Wu, Brian Morrow, Jennifer Nemeth-Seay, Ted Petley, Sam Wu, William R. Strohl, Anthony Simon Lynch, Victor J. Torres
Journal: Cell Host & Microbe (2023)

Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of virulence determinants, making it difficult to identify single targets for the development of vaccines or monoclonal therapies. We described a human-derived anti-S. aureus monoclonal antibody (mAb)-centyrin fusion protein ("mAbtyrin") that simultaneously targets multiple bacterial adhesins, resists proteolysis by bacterial protease GluV8, avoids Fc engagement by S. aureus IgG-binding proteins SpA and Sbi, and neutralizes pore-forming leukocidins via fusion with anti-toxin centyrins, while maintaining Fc- and complement-mediated functions. Compared with the parental mAb, mAbtyrin protected human phagocytes and boosted phagocyte-mediated killing. The mAbtyrin also reduced pathology, reduced bacterial burden, and protected from different types of infections in preclinical animal models. Finally, mAbtyrin synergized with vancomycin, enhancing pathogen clearance in an animal model of bacteremia. Altogether, these data establish the potential of multivalent mAbs for treating and preventing S. aureus diseases.
The natural product chlorotonil A preserves colonization resistance and prevents relapsing Clostridioides difficile infection
Authors: Arne Bublitz, Madita Brauer, Stefanie Wagner, Walter Hofer, Mathias Müsken, Felix Deschner, Till R. Lesker, Meina Neumann-Schaal, Lena-Sophie Paul, Ulrich Nübel, Jürgen Bartel, Andreas M. Kany, Daniela Zühlke, Steffen Bernecker, Rolf Jansen, Susanne Sievers, Katharina Riedel, Jennifer Herrmann, Rolf Müller, Thilo M. Fuchs, Till Strowig
Journal: Cell Host & Microbe (2023)

Clostridioides difficile infections (CDIs) remain a healthcare problem due to high rates of relapsing/recurrent CDIs (rCDIs). Breakdown of colonization resistance promoted by broad-spectrum antibiotics and the persistence of spores contribute to rCDI. Here, we demonstrate antimicrobial activity of the natural product class of chlorotonils against C. difficile. In contrast to vancomycin, chlorotonil A (ChA) efficiently inhibits disease and prevents rCDI in mice. Notably, ChA affects the murine and porcine microbiota to a lesser extent than vancomycin, largely preserving microbiota composition and minimally impacting the intestinal metabolome. Correspondingly, ChA treatment does not break colonization resistance against C. difficile and is linked to faster recovery of the microbiota after CDI. Additionally, ChA accumulates in the spore and inhibits outgrowth of C. difficile spores, thus potentially contributing to lower rates of rCDI. We conclude that chlorotonils have unique antimicrobial properties targeting critical steps in the infection cycle of C. difficile.
Blocking the CD47-SIRPα interaction reverses the disease phenotype in a polycythemia vera mouse model
Authors: Veronika Lysenko, Patrick M. Schürch, Selma Tuzlak, Nicole Wildner-Verhey van Wijk, Larisa V. Kovtonyuk, Burkhard Becher, Markus G. Manz, Stefanie Kreutmair, Alexandre P. A. Theocharides
Journal: Leukemia (2023)

Abstract Polycythemia vera (PV) is a hematopoietic stem cell neoplasm driven by somatic mutations in JAK2 , leading to increased red blood cell (RBC) production uncoupled from mechanisms that regulate physiological erythropoiesis. At steady-state, bone marrow macrophages promote erythroid maturation, whereas splenic macrophages phagocytose aged or damaged RBCs. The binding of the anti-phagocytic (“don’t eat me”) CD47 ligand expressed on RBCs to the SIRPα receptor on macrophages inhibits phagocytic activity protecting RBCs from phagocytosis. In this study, we explore the role of the CD47-SIRPα interaction on the PV RBC life cycle. Our results show that blocking CD47-SIRPα in a PV mouse model due to either anti-CD47 treatment or loss of the inhibitory SIRPα-signal corrects the polycythemia phenotype. Anti-CD47 treatment marginally impacted PV RBC production while not influencing erythroid maturation. However, upon anti-CD47 treatment, high-parametric single-cell cytometry identified an increase of MerTK+ splenic monocyte-derived effector cells, which differentiate from Ly6C hi monocytes during inflammatory conditions, acquire an inflammatory phagocytic state. Furthermore, in vitro, functional assays showed that splenic JAK2 mutant macrophages were more “pro-phagocytic,” suggesting that PV RBCs exploit the CD47-SIRPα interaction to escape innate immune attacks by clonal JAK2 mutant macrophages.
Genetic inhibition of glutamate allosteric potentiation of GABA<sub>A</sub>Rs in mice results in hyperexcitability, leading to neurobehavioral abnormalities
Authors: Yehong Du, Junjie Li, Maoju Wang, Qiuyun Tian, Yayan Pang, Ya Wen, Dongchuan Wu, Yu Tian Wang, Zhifang Dong
Journal: MedComm (2023)

Abstract The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ‐aminobutyric acid type A receptor (GABA A R)‐glutamate allosteric potentiation of GABA A R functions through a direct binding of glutamate to the GABA A R itself. Here, we investigated the physiological significance and pathological implications of this cross‐talk by generating the β3 E182G knock‐in (KI) mice. We found that β3 E182G KI, while had little effect on basal GABA A R‐mediated synaptic transmission, significantly reduced glutamate potentiation of GABA A R‐mediated responses. These KI mice displayed lower thresholds for noxious stimuli, higher susceptibility to seizures and enhanced hippocampus‐related learning and memory. Additionally, the KI mice exhibited impaired social interactions and decreased anxiety‐like behaviors. Importantly, hippocampal overexpression of wild‐type β3‐containing GABA A Rs was sufficient to rescue the deficits of glutamate potentiation of GABA A R‐mediated responses, hippocampus‐related behavioral abnormalities of increased epileptic susceptibility, and impaired social interactions. Our data indicate that the novel crosstalk among excitatory glutamate and inhibitory GABA A R functions as a homeostatic mechanism in fine‐tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning.